* T cells recognize antigens only in the form of peptides displayed by the products of self MHC genes on the surface of APCs. CD4+ helper T lymphocytes recognize antigens in association with class II MHC gene products (class II MHC-restricted recognition), and CD8+ CTLs recognize antigens in association with class I gene products (class I MHC-restricted recognition).
* Specialized APCs, such as dendritic cells, macrophages, and B lymphocytes, capture extracellular protein antigens, internalize and process them, and display class II-associated peptides to CD4+ T cells. Dendritic cells are the most efficient APCs for initiation of primary responses by activating naive T cells, and macrophages and B lymphocytes present antigens to differentiated helper T cells in the effector phase of cell-mediated immunity and in humoral immune responses, respectively. All nucleated cells can present class I-associated pep-tides, derived from cytosolic proteins such as viral and tumor antigens, to CD8+ T cells.
* The MHC is a large genetic region coding for class I and class II MHC molecules as well as for other proteins. MHC genes are highly polymorphic. Class
I MHC molecules are composed of an a (or heavy) chain in a noncovalent complex with a nonpoly-morphic polypeptide called ß2-microglobulin. The class II molecules contain two MHC-encoded polymorphic chains, an a chain and a ß chain. Both classes of MHC molecules consist of an extracellular peptide-binding cleft, a nonpolymorphic Ig-like region, a transmembrane region, and a cytoplasmic region. The peptide-binding cleft of MHC molecules has a-helical sides and an eight-stranded antiparallel ß-pleated sheet floor. The peptide-binding cleft of class I molecules is formed by the a1 and a2 segments of the a chain, and that of class
II molecules by the a1 and ß1 segments of the two chains. The Ig-like domains of class I and class II molecules contain the binding sites for the T cell coreceptors CD8 and CD4, respectively. The polymorphic residues of MHC molecules are localized to the peptide-binding domain.
* The function of MHC-encoded class I and class II molecules is to bind peptide antigens and display them for recognition by antigen-specific T lymphocytes. Peptide antigens associated with class I molecules are recognized by CD8+ T cells, whereas class II-associated peptide antigens are recognized by CD4+ T cells. MHC molecules bind only one peptide at a time, and all the peptides that bind to a particular MHC molecule share common structural motifs. Every MHC molecule has a broad specificity for peptides and can bind multiple pep-tides that have common structural features, such as anchor residues.
* The peptide-binding cleft of class I molecules can accommodate peptides that are 6 to 16 amino acid residues in length, whereas the cleft of class II molecules allows larger peptides (up to 30 amino acid residues in length or more) to bind. Some polymorphic MHC residues determine the binding specificities for peptides by forming structures, called pockets, that interact with complementary residues of the bound peptide, called anchor residues. Other polymorphic MHC residues and some residues of the peptide are not involved in binding to MHC molecules but instead form the structure recognized by T cells.
* Class I molecules are expressed on all nucleated cells, whereas class II molecules are expressed mainly on specialized APCs, such as dendritic cells, macrophages, and B lymphocytes, and a few other cell types, including endothelial cells and thymic epithelial cells. The expression of MHC gene products is enhanced by inflammatory and immune stimuli, particularly cytokines like IFN-y, which stimulate the transcription of MHC genes.
* Antigen processing is the conversion of native proteins into MHC-associated peptides. This process consists of the introduction of exogenous protein antigens into vesicles of APCs or the synthesis of antigens in the cytosol, the proteolytic degradation of these proteins into peptides, the binding of pep-tides to MHC molecules, and the display of the peptide-MHC complexes on the APC surface for recognition by T cells. Thus, both extracellular and intracellular proteins are sampled by these antigen-processing pathways, and peptides derived from both normal self proteins and foreign proteins are displayed by MHC molecules for surveillance by T lymphocytes.
* For class I-associated antigen presentation, cyto-solic proteins are proteolytically degraded in the proteasome, generating peptides with features that enable them to bind to class I molecules. These peptides are delivered from the cytoplasm to the ER by an ATP-dependent transporter called TAP. Newly synthesized class I MHC-P2-microglobulin dimers in the ER are associated with the TAP complex and receive peptides transported into the ER. Stable complexes of class I MHC molecules with bound peptides move out of the ER, through the Golgi complex, to the cell surface.
* For class II-associated antigen presentation, extracellular proteins are internalized into endosomes, where these proteins are proteolytically cleaved by enzymes that function at acidic pH. Newly synthesized class II MHC molecules associated with the Ii are transported from the ER to the endosomal vesicles. Here the Ii is proteolytically cleaved, and a small peptide remnant of the Ii, called CLIP, is removed from the peptide-binding cleft of the MHC molecule by the DM molecules. The peptides that were generated from extracellular proteins then bind to the available cleft of the class II MHC molecule, and the trimeric complex (class II MHC a and p chains and peptide) moves to and is displayed on the surface of the cell.
* These pathways of MHC-restricted antigen presentation ensure that most of the body's cells are screened for the possible presence of foreign antigens. The pathways also ensure that proteins from extracellular microbes preferentially generate pep-tides bound to class II MHC molecules for recognition by CD4+ helper T cells, which activate effector mechanisms that eliminate extracellular antigens. Conversely, proteins synthesized by intracellular (cytosolic) microbes generate peptides bound to class I MHC molecules for recognition by CD8+ CTLs, which function to eliminate cells harboring intracellular infections. The immunogenicity of foreign protein antigens depends on the ability of antigen-processing pathways to generate peptides from these proteins that bind to self MHC molecules.
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